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Author(s): N. Waugh, E. Cummins, D. S. Shyangdan, R. A. Court and
S. Mohiuddin
Article Title: Exenatide prolonged-release suspension for injection in
combination with oral antidiabetic therapy for the treatment of type 2
diabetes
Year of publication: 2012
Link to published article: http://www.nice.org.uk/ta248
Publisher statement: © National Institute for Health and Clinical
Excellence 2012. All rights reserved. NICE copyright material can be
downloaded for private research and study, and may be reproduced for
educational and not-for-profit purposes. No reproduction by or for
commercial organisations, or for commercial purposes, is allowed
without the written permission of NICE.
Exenatide prolonged-release
suspension for injection in
combination with oral
antidiabetic therapy for the
treatment of type 2 diabetes
Issued: February 2012
NICE technology appraisal guidance 248
www.nice.org.uk/ta248
NHS Evidence has accredited the process used by the Centre for Health Technology Evaluation at
NICE to produce technology appraisals guidance. Accreditation is valid for 3 years from September
2009 and applies to guidance produced since June 2008 using the processes described in NICE's
'The guide to the methods of technology appraisal' (2008). More information on accreditation can be
viewed at www.evidence.nhs.uk
Copyright © NICE 2012
Exenatide prolonged-release suspension for injection in
combination with oral antidiabetic therapy for the treatment of type 2
diabetes
NICE technology
appraisal guidance
248
Contents
1 Guidance ..................................................................................................................................
3
2 The technology ........................................................................................................................
5
3 The manufacturer's submission................................................................................................
6
Clinical effectiveness.............................................................................................................................
6
Cost effectiveness ................................................................................................................................. 12
Evidence Review Group comments ...................................................................................................... 19
Evidence Review Group exploratory analyses...................................................................................... 21
4 Consideration of the evidence .................................................................................................. 22
Summary of Appraisal Committee's key conclusions............................................................................ 36
5 Implementation ......................................................................................................................... 44
6 Recommendations for further research .................................................................................... 45
7 Related NICE guidance ............................................................................................................ 46
8 Review of guidance ................................................................................................................. 47
Appendix A: Appraisal Committee members, and NICE project team ........................................ 48
A Appraisal Committee members.......................................................................................................... 48
B NICE project team.............................................................................................................................. 50
Appendix B: Sources of evidence considered by the Committee................................................ 51
About this guidance ..................................................................................................................... 54
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1 Guidance
1.1
Prolonged-release exenatide in triple therapy regimens (that is, in combination
with metformin and a sulphonylurea, or metformin and a thiazolidinedione) is
recommended as a treatment option for people with type 2 diabetes as
described in 'Type 2 diabetes: the management of type 2 diabetes (NICE
clinical guideline 87); that is, when control of blood glucose remains or
becomes inadequate (HbA1c ≥ 7.5% [59 mmol/mol] or other higher level agreed
with the individual), and the person has:
a body mass index (BMI) ≥ 35 kg/m2 in those of European family origin (with
appropriate adjustment for other ethnic groups) and specific psychological or
medical problems associated with high body weight or
a BMI < 35 kg/m2, and therapy with insulin would have significant occupational
implications or weight loss would benefit other significant obesity-related
comorbidities.
1.2
Treatment with prolonged-release exenatide in a triple therapy regimen should
only be continued as described in 'Type 2 diabetes: the management of type 2
diabetes' (NICE clinical guideline 87); that is, if a beneficial metabolic response
has been shown (defined as a reduction of at least 1 percentage point in HbA1c
[11 mmol/mol] and a weight loss of at least 3% of initial body weight at
6 months).
1.3
Prolonged-release exenatide in dual therapy regimens (that is, in combination
with metformin or a sulphonylurea) is recommended as a treatment option for
people with type 2 diabetes, as described in 'Liraglutide for the treatment of
type 2 diabetes mellitus' (NICE technology appraisal 203); that is, only if:
the person is intolerant of either metformin or a sulphonylurea, or a treatment with
metformin or a sulphonylurea is contraindicated, and
the person is intolerant of thiazolidinediones and dipeptidyl peptidase-4 (DPP-4)
inhibitors, or a treatment with thiazolidinediones and DPP-4 inhibitors is
contraindicated.
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Exenatide prolonged-release suspension for injection in
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1.4
NICE technology
appraisal guidance
248
Treatment with prolonged-release exenatide in a dual therapy regimen should
only be continued as described in 'Liraglutide for the treatment of type 2
diabetes mellitus' (NICE technology appraisal guidance 203); that is, if a
beneficial metabolic response has been shown (defined as a reduction of at
least 1 percentage point in HbA1c [11 mmol/mol] at 6 months).
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2 The technology
2.1
Exenatide prolonged-release suspension for injection (Bydureon, Eli Lilly) has
a UK marketing authorisation for the 'treatment of type 2 diabetes mellitus in
combination with:
metformin
sulphonylurea
thiazolidinedione
metformin and sulphonylurea
metformin and thiazolidinedione
in adults who have not achieved adequate glycaemic control on maximally tolerated
doses of these oral therapies'. The recommended dose is 2 mg exenatide once
weekly by subcutaneous injection. Exenatide is a glucagon-like peptide-1 (GLP-1)
receptor agonist. Incretin hormones such as GLP-1 enhance glucose-dependent
insulin secretion and exhibit other antihyperglycaemic actions. Exenatide improves
glycaemic control in patients with type 2 diabetes in several ways, including through
enhanced glucose-dependent insulin secretion, and reduced glucose-dependent
glucagon secretion.
2.2
The most common adverse drug reactions are mainly gastrointestinal (nausea,
vomiting, diarrhoea and constipation), injection site reactions (pruritus,
nodules, erythema), hypoglycaemia (with a sulphonylurea), and headache can
also occur. Most adverse reactions are mild to moderate in intensity. For full
details of side effects and contraindications, see the summary of product
characteristics.
2.3
Exenatide prolonged-release suspension for injection costs £73.36 for a pack
of four single-dose kits, each containing one vial of exenatide 2 mg powder
and a pre-filled syringe of solvent (costs from manufacturer's submission;
excludes VAT). Costs may vary in different settings because of negotiated
procurement discounts.
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3 The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of
exenatide prolonged-release suspension for injection and a review of this submission by the
Evidence Review Group (ERG; appendix B).
Clinical effectiveness
3.1
The manufacturer's submission presented evidence on the clinical
effectiveness of weekly prolonged-release exenatide (2 mg subcutaneous
injection) in patients with type 2 diabetes that was inadequately controlled with
oral therapy and/or lifestyle modification based on the DURATION trial
programme. Five randomised controlled trials compared weekly prolongedrelease exenatide 2 mg with either exenatide 10 micrograms twice daily
(DURATION-1 and DURATION-5), sitagliptin 100 mg (DURATION-2),
pioglitazone 45 mg (DURATION-2), insulin glargine once daily (DURATION-3)
or liraglutide 1.8 mg (DURATION-6).
3.2
The primary outcome for all studies was change in HbA1c from baseline to end
point (24–30 weeks). Secondary outcomes included changes in body weight,
and safety and tolerability. Results were reported for the intention-to-treat
populations. Three of the trials had an open-ended extension period
(DURATION-1, DURATION-2 and DURATION-3).
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3.3
NICE technology
appraisal guidance
248
Patients in the trials were broadly similar: aged at least 18 years with a
baseline body mass index 25–45 kg/m2, HbA1c 7.1–11.0% at screening and
stable body weight. Patients enrolled in the DURATION studies were on a mix
of different background treatments. Patients in DURATION-1 and
DURATION-5 were on a wide range of treatments including diet and exercise
alone, metformin alone, metformin and sulphonylurea, thiazolidinedione alone
and metformin and thiazolidinedione. Patients in DURATION-3 were either on
metformin alone (approximately 70%) or metformin and sulphonylurea
(approximately 30%). All patients in DURATION-2 were on metformin alone as
background therapy. Information on the background treatments in the
DURATION-6 trial which compared prolonged-release exenatide with
liraglutide 1.8 mg were submitted as academic in confidence and therefore,
have not been presented here. The effectiveness of weekly prolonged-release
exenatide 2 mg was compared with exenatide 10 micrograms twice daily in two
studies, which demonstrated both reductions in HbA1c and body weight. In both
studies, HbA1c reduction was greater with the once-weekly preparation. In
DURATION-1 (n = 295), reduction in HbA1c was −1.9% for weekly prolongedrelease exenatide versus −1.5% for exenatide twice daily (p = 0.0023). In
DURATION-5 (n = 252), reduction in HbA1c was −1.6% for weekly prolongedrelease exenatide versus –0.9% for exenatide twice daily (p < 0.0001). Weight
loss was similar for the weekly prolonged-release and twice-daily arms in both
studies (−3.7 kg for weekly prolonged-release exenatide and −3.6 kg for
exenatide twice daily in DURATION-1, p = 0.8916; −2.3 kg for weekly
prolonged-release exenatide and −1.4 kg for exenatide twice daily in
DURATION-5, p = 0.0514). The Diabetes Treatment Satisfaction Questionnaire
(DTSQ) and Impact of Weight on Quality of Life Questionnaire, Lite Version
(IWQOL-Lite) showed significant improvements from baseline in both
treatment arms (p < 0.001 both comparisons) but without any statistically
significant differences between the treatment arms.
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3.4
DURATION-2 (n = 491) compared the effectiveness of weekly prolongedrelease exenatide 2 mg plus oral placebo with sitagliptin 100 mg plus injected
placebo, and with pioglitazone 45 mg orally plus injected placebo. There was a
statistically significant greater reduction in HbA1c with weekly prolongedrelease exenatide (−1.55%) compared with sitagliptin (0.92%, p < 0.0001) and
pioglitazone (−1.23%, p = 0.0165). Weekly prolonged-release exenatide was
associated with a weight loss of 2.3 kg compared with a weight loss of 0.8 kg
for sitagliptin (p = 0.0002) and a weight gain of 2.8 kg for pioglitazone
(p < 0.0001). Significantly greater improvements in IWQOL-Lite total score
were reported for weekly prolonged-release exenatide versus pioglitazone
(difference 3.94, 95% confidence interval [CI] 1.28 to 6.61, p = 0.0038). All
treatment groups showed statistically significant improvements from baseline
on the Psychological and General Well-being Index (PGWB) and DTSQ total
scores, with greater improvement in overall treatment satisfaction for weekly
prolonged-release exenatide versus sitagliptin (difference 1.61, 95% CI 0.07 to
3.16, p = 0.0406).
3.5
Weekly prolonged-release exenatide 2 mg versus insulin glargine once daily
was investigated in the DURATION-3 trial (n = 456). There was a statistically
significant greater reduction in HbA1c for weekly prolonged-release exenatide
compared with insulin glargine (−1.47% versus −1.31%, p = 0.017). Weekly
prolonged-release exenatide was associated with a weight loss of 2.6 kg
compared with a weight gain of 1.4 kg for insulin glargine (p < 0.001). Patients
in both treatment groups reported improvements from baseline to end point in
IWQOL-Lite, Binge Eating Scale (BES) and DTSQ total scores. Patients on
weekly prolonged-release exenatide showed statistically significant gains in
health-related quality of life as measured by EQ-5D. There was no statistically
significant difference in quality of life between the weekly prolonged-release
exenatide and insulin glargine arms for any of the measures of quality of life.
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3.6
Weekly prolonged-release exenatide 2 mg was compared with liraglutide
1.8 mg once daily in the DURATION-6 study (n = 911). There was a statistically
significant greater reduction in HbA1c with liraglutide 1.8 mg (−1.48%)
compared with weekly prolonged-release exenatide (−1.28%, p = 0.002).
There was a statistically significant greater weight loss with liraglutide 1.8 mg
(−3.6 kg) compared with weekly prolonged-release exenatide (−2.7 kg,
p < 0.001). The manufacturer presented confidential evidence on differences in
quality of life that cannot be included.
3.7
The extension studies (DURATION-1, DURATION-2 and DURATION-3)
showed continuation of the benefits of treatment with weekly prolongedrelease exenatide. In DURATION-1, patients who completed 52 weeks of
treatment with weekly prolonged-release exenatide had similar HbA1c reduction
to those who switched from exenatide twice daily to weekly prolonged-release
exenatide at week 30. Patients who continued treatment with weekly
prolonged-release exenatide reported a statistically significant HbA1c reduction
from baseline at 2 years and at 3 years. In DURATION-2, initial 26-week
improvements in HbA1c with weekly prolonged-release exenatide were
sustained at week 52. HbA1c reduction was also sustained at week 52 in
patients who switched from pioglitazone, while switching from sitagliptin
increased the reduction in HbA1c at 52 weeks (−1.4%). The difference in weight
change between the weekly prolonged-release exenatide and insulin glargine
groups was maintained at 84 weeks in the DURATION-3 trial.
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3.8
The manufacturer presented the effectiveness of weekly prolonged-release
exenatide for pre-specified subgroups that were defined by baseline HbA1c
(less than 9%, or 9% or greater). Weekly prolonged-release exenatide was
associated with a statistically significant reduction in HbA1c compared with
exenatide twice daily and sitagliptin (but not pioglitazone) for both subgroups.
For the comparison of weekly prolonged-release exenatide with pioglitazone,
the reduction in HbA1c reached statistical significance only in patients with
HbA1c of 9% or greater. There was a numerically greater HbA1c reduction with
weekly prolonged-release exenatide in the subgroups with baseline HbA1c 9%
or greater than in the subgroups with HbA1c less than 9% versus exenatide
twice daily, sitagliptin and pioglitazone. The manufacturer also presented
confidential evidence about HbA1c subgroups from the DURATION-6 trial
(weekly prolonged-release exenatide compared with liraglutide 1.8 mg) that
cannot be included in this document.
3.9
The manufacturer presented the effectiveness of weekly prolonged-release
exenatide for subgroups defined by baseline body mass index (less than
30 kg/m2, 30 to 35 kg/m2 and greater than 35 kg/m2). A post-hoc analysis of
HbA1c reduction by body mass index category indicated that there was no
relationship between HbA1c reduction and body mass index associated with
weekly prolonged-release exenatide treatment.
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3.10
NICE technology
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248
A network meta-analysis was included to compare the clinical effectiveness of
weekly prolonged-release exenatide with liraglutide 1.2 mg (the dose
recommended in 'Liraglutide for the treatment of type 2 diabetes' [NICE
technology appraisal guidance 203]). A systematic literature review identified
19 randomised controlled trials of weekly prolonged-release exenatide and
liraglutide that had common comparators (exenatide twice daily, insulin
glargine and placebo). The manufacturer reported the relative effectiveness of
each active treatment compared with placebo. All active treatments produced
statistically significant reductions in HbA1c. A head-to-head analysis of weekly
prolonged-release exenatide versus liraglutide at the different doses was
performed. The results of the adjusted analysis for mean difference (95% CI) in
HbA1c versus placebo showed that liraglutide 1.8 mg was associated with the
biggest reduction in HbA1c (−1.18% [−1.32 to −1.04]) followed by weekly
prolonged-release exenatide (−1.15% [−1.31 to −1.00]), liraglutide 1.2 mg
(−1.01% [−1.18 to −0.85]), insulin glargine (−0.84% [−1.00 to −0.67]) and
exenatide twice daily (−0.82% [−0.94 to −0.70]). Results followed the same
trend when controlling for background oral therapy. The manufacturer noted
that this demonstrates that the efficacy of weekly prolonged-release exenatide
is not statistically significantly different from liraglutide (both 1.2 mg and 1.8 mg
doses) in relation to HbA1c reduction. The head-to-head network meta-analysis
also reported no significant difference between the comparative efficacy of
weekly prolonged-release exenatide and liraglutide (1.2 mg and 1.8 mg doses)
for weight change or systolic blood pressure.
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Adverse events
3.11
The most common adverse effects (occurring in more than 5% of patients)
associated with weekly prolonged-release exenatide in the DURATION trials
were nausea, diarrhoea and vomiting. The manufacturer noted that the drug
was generally well-tolerated; adverse events were generally mild or moderate
and were of a similar type and frequency to those observed with exenatide
twice daily. Additionally, the rate of adverse events did not vary with
background oral antidiabetic therapy (with the exception of a higher incidence
of hypoglycaemia with concomitant sulphonylurea use). Weekly prolongedrelease exenatide was associated with a lower incidence of gastrointestinal
adverse events (35% versus 14–26%) but a higher incidence of injection siterelated events compared with exenatide twice daily. Weekly prolonged-release
exenatide was associated with low rates of minor hypoglycaemic events
(1–3%) in patients who were not taking a concomitant sulphonylurea.
Cost effectiveness
3.12
The manufacturer submitted a de novo analysis using the CORE diabetes
model to assess the cost effectiveness of weekly prolonged-release exenatide
in treating type 2 diabetes that is inadequately controlled on oral antidiabetic
therapy, from an NHS and personal social services perspective. In the model,
weekly prolonged-release exenatide was used as an alternative to liraglutide
1.2 mg in dual therapy regimens where sulphonylureas, thiazolidinediones and
DPP-4 inhibitors are not tolerated or are contraindicated, and as part of triple
therapy (as an alternative to exenatide twice daily and liraglutide 1.2 mg).
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3.13
The CORE model consists of 15 Markov submodels that simulate the major
macrovascular and microvascular complications of type 2 diabetes. Patients
enter the model at the point where glycaemic control is inadequate on current
treatment and they are about to move to the next step in the treatment
pathway. The model projects long-term outcomes by taking into consideration
baseline patient characteristics (such as ethnicity, gender, age, body mass
index, duration of diabetes), past history of complications (for example,
previous myocardial infarction or stroke) and physiological parameters (for
example, HbA1c, systolic blood pressure and lipids). Each submodel runs
simultaneously and in parallel, allowing patients to develop multiple
complications within each Markov cycle and over the entire duration of the
model.
3.14
The manufacturer incorporated data from the DURATION-1, DURATION-2,
DURATION-3 and DURATION-5 clinical trials and the network meta-analysis in
the economic analyses. Because the trials included a mix of background
treatments, the manufacturer assumed that the treatment effects were
comparable regardless of their place in treatment (dual and triple therapy) and
independent of the stage of disease. Comparators were exenatide twice daily,
sitagliptin, pioglitazone, insulin glargine and liraglutide 1.2 mg. Liraglutide
1.8 mg was not included because this dose was not recommended by NICE
(NICE technology appraisal guidance 203) so data from the network metaanalysis were used. Six-month data from the DURATION trials were used to
populate the model at 1 year and the treatment effect was assumed to be
maintained for 5 years until switching to insulin glargine, in line with the
modelling in 'Type 2 diabetes: the management of type 2 diabetes' (NICE
clinical guideline 87) and NICE technology appraisal guidance 203.
3.15
Within each submodel, patient characteristics (for example, HbA1c level) were
used in risk equations to calculate the probability of experiencing diabetes
complications. The risk of experiencing an event was further modified by use
and effectiveness of medications, screening (for example, for foot problems or
eye complications), and concomitant treatments (for example, aspirin, statins
or angiotensin-converting enzyme inhibitors).
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3.16
After switching to insulin glargine, two different situations were modelled
depending on the initial treatment effect. If one treatment caused weight loss
and the other caused weight gain (for example, with weekly prolonged-release
exenatide compared with pioglitazone and insulin glargine), no change was
applied after switching for treatments with initial weight gain but the body mass
index reverted to baseline immediately after switching for treatments with initial
weight loss. If both treatments caused weight loss (for example, with weekly
prolonged-release exenatide compared with sitagliptin, exenatide twice daily
and liraglutide), the body mass index for both treatment groups reverted to
baseline immediately after switching. The CORE model is not set up to model
changes over time, therefore changes in body mass index observed in the
DURATION trials were applied to the starting cohort.
3.17
Common adverse events were incorporated using incidence rates for nausea
and hypoglycaemia from the DURATION trials. The model applied a 6-month
disutility for nausea for each comparator and this assumption was tested in the
sensitivity analyses. Disutility and associated costs for hypoglycaemic events
(included as minor events because there were no events that met the CORE
model definition of major hypoglycaemic events) were applied for 5 years until
treatment was switched to insulin glargine. The model did not include a
disutility associated with injection site reactions in the base case because the
DURATION trials showed that injection site reactions were mild and transient
and incidence rates were low, although a sensitivity analysis that assessed the
impact of this adverse event was also provided.
3.18
The risk equations for developing long-term complications were predominantly
based on long-term outcome data from the UKPDS and Framingham studies.
The model ran in 1-year cycles (after each cycle the profile of each patient was
updated for the occurrence of complications and disease progression then
used in the next cycle). Exceptions were the foot ulcer/amputation submodel
(3-month cycles) and the hypoglycaemia submodel (3-month and 1-day cycles
for major and minor events respectively). Each submodel used tracker
variables to overcome the memoryless properties of standard Markov models,
and allowed interconnectivity and interaction between individual complication
submodels.
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3.19
Base-case assumptions used in the manufacturer's model incorporated a time
horizon of 50 years. The first five cycles in the model equated to 5 years of
treatment with either weekly prolonged-release exenatide or comparator, then
patients in both arms switched to insulin glargine. The base-case model did not
incorporate a reduction in HbA1c after switching because treatment effects
were applied equally to both arms. For the remaining 45 cycles (from year 6
onwards), the model continued to evaluate utilities and costs from the
associated disease complications.
3.20
Utility values for the different health states and complications of diabetes were
mostly taken from the guidance on liraglutide in type 2 diabetes (NICE
technology appraisal guidance 203) and from NICE clinical guideline 87. A
utility value of 0.814 was used as the baseline quality of life value in the model
for patients with type 2 diabetes who were free of complications (derived from
EQ-5D data in the UKDPS trial). In the model, each health state had a utility
value. A total disutility value of −0.04 was used for the subset of patients
experiencing nausea and was weighted across the entire population for the
first 6 months. For each occurrence of hypoglycaemia, the appropriate disutility
relating to minor or major events was applied (−0.012 for major event; −0.004
for a minor event). Injection site reactions were incorporated into the economic
analysis via a decrease in utility of −0.011. The decrease in utility was applied
for 5 years and weighted across the entire population for each treatment arm
according to the proportion of patients who experienced the adverse event
from each of the clinical trials. Patients experienced a decrease in their quality
of life when they had an event or complication, which was updated after each
cycle. For multiple comorbidities, the model selected the utility of the lowest
value and used it in subsequent cycles.
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3.21
The manufacturer used unit costs from the NICE guidance on liraglutide (NICE
technology appraisal guidance 203) where possible for consistency and
reference costs were inflated to 2010 levels where appropriate. Total
treatment-related costs for type 2 diabetes comprised drug costs and
consumable costs (costs associated with self-monitoring of blood glucose and
costs of needles for injectable therapies). The frequency of blood glucose
monitoring was assumed to be 1 test per day for patients taking insulin and
3 tests per week for patients receiving a sulphonylurea at a cost of £0.33 per
test.
3.22
Drug acquisition costs for comparators were taken from MIMS (April 2011
edition). Costs of background oral therapies were not included because these
were the same across treatment arms in each respective trial. Total annual
costs for year 1 to year 5 were £515.00 for pioglitazone 45 mg, £434.65 for
sitagliptin 100 mg, £911.99 for exenatide 10 micrograms twice daily (drug costs
£829.12), £466.68 for insulin glargine 31.1 IU/day (drug costs £314.12) and
£1022.95 for liraglutide 1.2 mg (drug costs £956.96). The total annual cost for
weekly prolonged-release exenatide differed across the DURATION studies
because blood glucose monitoring requirements were not the same in all trials.
Drug costs for weekly prolonged-release exenatide were £956.96 for all
studies with additional costs of £17.13 for DURATION-1 and DURATION-5,
£15.14 for DURATION-3 and £33.13 for the comparison with liraglutide 1.2 mg.
For treatment with insulin glargine (40.0 IU/day) from year 6 onwards, drug
costs were £405.43 and total costs were £557.99. No costs were attributed to
managing the adverse events included in the model because it is not expected
to need NHS resources.
3.23
The manufacturer's base-case results showed that weekly prolonged-release
exenatide was more costly but was associated with greater life expectancy and
more quality-adjusted life years (QALYs) than pioglitazone, sitagliptin and
insulin glargine, giving incremental cost-effectiveness ratios (ICERs) of £8624,
£6554 and £11,041 per QALY gained respectively. Weekly prolonged-release
exenatide dominated exenatide twice daily and liraglutide 1.2 mg because it
was associated with greater benefits at a lower cost. Dominance over
liraglutide 1.2 mg was the result of a slightly larger predicted reduction in HbA1c
with weekly prolonged-release exenatide and reduced needle costs.
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3.24
A probabilistic sensitivity analysis presented by the manufacturer showed that,
at a threshold of £20,000 per QALY, weekly prolonged-release exenatide had a
99–100% probability of being cost effective when compared with pioglitazone,
sitagliptin, exenatide twice daily and insulin glargine, and an 87.4% probability
of being cost effective compared with liraglutide 1.2 mg.
3.25
The manufacturer presented a range of deterministic sensitivity analyses
around the confidence limits within the weekly prolonged-release exenatide
arm for the main clinical parameters (HbA1c, blood pressure, lipids and body
mass index), complication costs and utilities. The ICERs were not sensitive to
changes in most of the clinical efficacy, costs and utilities parameters, which
generally produced ICERs of under £10,000 per QALY gained for weekly
prolonged-release exenatide compared with pioglitazone and sitagliptin, and
ICERs of under £14,000 per QALY gained in comparison with insulin glargine.
The key drivers of the cost effectiveness of weekly prolonged-release
exenatide were the effects on HbA1c and weight, although all of the ICERs for
the sensitivity analysis were below £15,000 per QALY gained. Weekly
prolonged-release exenatide dominated liraglutide 1.2 mg in all of the analyses
with the exception of when HbA1c was set to the lower 95% confidence interval,
which led to liraglutide 1.2 mg dominating weekly prolonged-release exenatide.
In response to a request by the ERG, the manufacturer conducted a sensitivity
analysis that applied the cost of human NPH insulin to the cost-effectiveness
estimate of weekly prolonged-release exenatide compared with insulin. This
reduced total costs in both arms but increased the net cost from £1709 to
£2544 for the prolonged-release exenatide arm over the insulin arm, increasing
the ICER of weekly prolonged-release exenatide to £16,493 per QALY gained.
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3.26
The manufacturer also performed subgroup analyses according to body mass
index (30 kg/m2 or less, greater than 30 kg/m2, at least 30 kg/m2 but less than
35 kg/m2, and 35 kg/m2 or greater) and HbA1c (baseline HbA1c less than 9% or
at least 9%). Weekly prolonged-release exenatide was cost effective in each
body mass index subgroup compared with pioglitazone, sitagliptin and insulin
glargine (with the majority of ICERs being under £10,000 per QALY gained),
and continued to dominate exenatide twice daily (that is, weekly prolongedrelease exenatide was more effective and less costly). Weekly prolongedrelease exenatide was cost effective in both HbA1c subgroups for comparisons
with pioglitazone, sitagliptin and insulin glargine, although weekly prolongedrelease exenatide was more cost effective in patients with a baseline HbA1c of
equal to or greater than 9% (no comparison was made with liraglutide 1.2 mg).
3.27
Structural sensitivity analyses, which were conducted by the manufacturer to
explore assumptions within the model, yielded results that were all within a
relatively narrow range of the base-case estimated cost per QALY and were all
below £20,000 per QALY gained. This suggested that the economic modelling
is robust to the structural assumptions used.
3.28
A scenario analysis was conducted that applied a treatment continuation rule
(based on NICE clinical guideline 87), in which patients only continued
treatment if they had a beneficial metabolic response (a reduction of at least 1
percentage point in HbA1c and a weight loss of at least 3% of initial body weight
at 6 months). Patients who achieved the treatment continuation criteria in
either the prolonged-release exenatide or comparator arm continued treatment
for 5 years before switching to insulin glargine (base case). The other patients
switched to insulin glargine after 1 year. The ICERs improved for weekly
prolonged-release exenatide compared with pioglitazone (£2519 per QALY
gained versus £8624 per QALY gained in the base case), sitagliptin (£1793 per
QALY gained versus £6554 per QALY gained in the base case) and insulin
glargine (£5593 per QALY gained versus £11,041 per QALY gained in the base
case).
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Evidence Review Group comments
3.29
The ERG noted all of the relevant studies had been included in the
manufacturer's submission and that they were all of good quality.
3.30
The ERG commented on the suitability of the DURATION trials for addressing
the decision problem. They noted that the populations in the DURATION-1 and
DURATION-5 trials do not fully reflect the use of GLP-1 analogues in clinical
practice (triple therapy). Patients in these trials were taking a range of
background treatments, with 43–46% receiving monotherapy and 36–39% dual
therapy. The ERG also did not consider the DURATION-2 trial, which
compared weekly prolonged-release exenatide with pioglitazone and
sitagliptin, to be relevant to UK clinical practice because patients in the trial
were taking metformin monotherapy and were randomised to receive dual
therapy with metformin plus either weekly prolonged-release exenatide,
sitagliptin or pioglitazone. It noted that this is at variance with NICE clinical
guideline 87, which recommends adding a sulphonylurea (or oral alternative
such as pioglitazone) to metformin. The ERG also advised that in routine care
a (relatively) inexpensive oral drug would be offered before an expensive
injectable drug. The ERG, however, considered the DURATION-6 trial (which
used a 1.8 mg daily dose of liraglutide as the comparator) better reflects
clinical practice because 64% of the patients were receiving dual therapy.
3.31
The ERG considered the network meta-analysis that compared weekly
prolonged-release exenatide with liraglutide 1.2 mg to be consistent with the
scope for this appraisal, noting that it was good quality and showed similar
efficacy between the two drugs, although there was a small disutility
associated with additional injections with liraglutide. The ERG noted that the
size of the difference in HbA1c between the liraglutide doses (1.2 mg and
1.8 mg) could hypothetically affect the cost-effectiveness calculations. The
ERG's meta-analysis (which excluded a monotherapy trial that was included in
the manufacturer's analysis) estimated that the difference in HbA1c was 0.10%
compared with the manufacturer's estimate of 0.17%.
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3.32
The ERG considered that there may be some structural uncertainty around the
CORE model because it appeared to model the evolution of HbA1c, systolic
blood pressure and the ratio of total cholesterol to HDL cholesterol quite
differently to the UKPDS outcomes model. In particular, CORE appeared to
maintain a proportion of the initial net effects between the treatment arms
indefinitely, whereas the UKPDS outcomes model appeared to model these
net effects as tending to zero over time. The ERG also considered that there
was uncertainty in the assumption that treatment duration will be 5 years
because of the absence of long-term clinical data.
3.33
The ERG considered the direct health-related quality of life impact from
changes in body mass index to be a model driver because its exclusion
increased the ICER for weekly prolonged-release exenatide when compared
with pioglitazone (£17,772 per QALY gained compared with £8624 per QALY
gained in the base case) and insulin glargine (£16,605 per QALY gained
compared with £11,041 per QALY gained in the base case). The ERG
observed that assumed duration of therapy is also a model driver, with cost
effectiveness improving with a shorter duration of therapy before switching.
The ERG noted that all the modelling found that weekly prolonged-release
exenatide produced similar patient benefits and costs as liraglutide 1.2 mg,
although the sensitivity analyses demonstrated that the small net effects cause
the analysis to swing from the base case of weekly prolonged-release
exenatide dominating liraglutide 1.2 mg to it sometimes being dominated by
liraglutide 1.2 mg.
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Evidence Review Group exploratory analyses
3.34
The ERG noted that the model applied lifetime weight changes, which may
bias against treatments that increase weight. The ERG undertook sensitivity
and scenario analyses on the manufacturer's model to investigate the impact
of lifetime maintenance of weight gain on health-related quality of life and the
impact of individual clinical effects. A sensitivity analysis in which the disutility
associated with increasing weight was only applied for 5 years (that is, before
switching treatment to insulin glargine) increased the ICER of weekly
prolonged-release exenatide from £8624 per QALY gained to £12,052 per
QALY gained for the comparison with pioglitazone and from £11,041 per QALY
gained to £12,839 per QALY gained for the comparison of weekly prolongedrelease exenatide with insulin glargine.
3.35
The ERG investigated how the individual clinical effects (changes in body
mass index [with and without applying any direct disutility from weight
changes], HbA1c, systolic blood pressure, and cholesterol and triglycerides)
observed within the DURATION trials contributed to anticipated patient
outcomes and costs. For the comparisons of weekly prolonged-release
exenatide with exenatide twice daily, the ERG considered the main benefit to
be derived from changes in HbA1c, with lipid changes also contributing.
Changes in HbA1c had the greatest effect on cost. For the comparison with
pioglitazone, the patient benefits were shared almost equally between the
direct impact of weight changes and changes in HbA1c. Costs were
predominantly reduced because lower HbA1c levels will reduce complication
rates. For the comparison with insulin glargine, the largest patient benefit was
from the direct impact of weight changes, but only the change in HbA1c
significantly affected costs. For the comparison with liraglutide 1.2 mg, only
HbA1c has any significant impact on both benefits and costs.
3.36
Full details of all the evidence are in the manufacturer's submission and the
ERG report.
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4 Consideration of the evidence
4.1
The Appraisal Committee reviewed the data available on the clinical and cost
effectiveness of weekly prolonged-release exenatide, having considered
evidence on the nature of type 2 diabetes and the value placed on the benefits
of weekly prolonged-release exenatide by people with the condition, those who
represent them, and clinical specialists. It also took into account the effective
use of NHS resources.
4.2
The Committee discussed the clinical treatment pathway for type 2 diabetes.
The aim of treatment is to achieve good control of blood glucose levels (which
is reflected in HbA1c levels) whilst minimising complications such as weight gain
and hypoglycaemia. The Committee heard from clinical specialists that the
choice of treatment is individualised for each patient, and that current UK
practice broadly follows NICE guidance (NICE clinical guideline 87) which
recommends a stepwise approach that includes using diet and exercise,
various antidiabetic drugs and insulin. The Committee heard from clinical
specialists that the understanding of the precise mode of action of GLP-1
agonists is still evolving. If GLP-1 agonists simply stimulated islet cells, they
would not be expected to have significant therapeutic benefit at a late stage of
the disease, which nevertheless appears to be the case. The Committee also
heard from clinical specialists that there is a trend towards reduced use of
sulphonylurea (because of the associated weight gain and the high incidence
of hypoglycaemia compared with other oral treatments) and pioglitazone
(because of long-term safety concerns over bladder cancer). The Committee
was aware that clinical opinion was moving away from sulphonylurea use but
also noted that it had been decided that NICE clinical guideline 87 should be
updated (expected publication date to be confirmed) and anticipated that
changing trends in diabetes management would be addressed in the updated
guidance when the whole evidence base had been reviewed. There would also
be an opportunity to review the weight and other criteria for initiating GLP-1
agonists in the guidance.
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4.3
The Committee heard evidence from the patient expert that people with type 2
diabetes may be reluctant to start treatment with insulin or wish to avoid insulin
therapy because of fear of hypoglycaemia and its impact on their lifestyle (for
example, the threat of losing their driving licence). The patient expert stated
the main benefits of weekly prolonged-release exenatide to be improved
quality of life associated with a once-weekly treatment regimen, which would
reduce the lifestyle impact of managing type 2 diabetes, as well as improved
glycaemic control and weight loss, which are also seen with other GLP-1
agonists. The Committee heard from the patient expert that a once-weekly
regimen would be advantageous for patients who rely on a carer to administer
treatment because they are unable to self-administer injections. The
Committee recognised the demands that managing type 2 diabetes places on
patients and concluded that an effective once-weekly regimen would be
associated with important potential benefits for patients but that on current
evidence GLP-1 agonists would not replace insulin (although they may offer an
opportunity to delay insulin therapy in some patients).
4.4
The Committee considered the evidence submitted by the manufacturer on the
clinical effectiveness of weekly prolonged-release exenatide, noting that the
evidence came from five clinical trials and a network meta-analysis. The
Committee considered the comparators included in the trials for triple therapy
to be generally appropriate but noted that insulin glargine was the comparator
in the DURATION-3 trial instead of human NPH insulin, which is recommended
for routine use in NICE clinical guideline 87. The Committee considered the
comparators used in the trials with dual therapy to be broadly appropriate but
noted the significant absence of a trial comparing weekly prolonged-release
exenatide with a sulphonylurea. The Committee concluded that the
comparators in the DURATION trials were broadly, but not specifically, relevant
to clinical practice in the UK.
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4.5
The Committee considered the patient populations included in the clinical
trials. The Committee noted that patients were taking a mix of different
background treatments comprising lifestyle modification and different drug
regimens in three of the trials (DURATION-1, DURATION-5 and
DURATION-6). It particularly noted that the trials which compared weekly
prolonged-release exenatide with exenatide twice daily (DURATION-1 and
DURATION-5) included patients who were treated by diet and exercise alone.
It also noted that the range of background treatments produced up to eight
subgroups with different background treatments in each of these two trials. In
addition, in the trial that compared weekly prolonged release exenatide with
insulin glargine (DURATION-3), 70% of patients were taking metformin alone
as background treatment whereas NICE clinical guideline 87 recommends
adding a second oral agent to metformin before adding insulin. DURATION-2
compared the addition of weekly prolonged-release exenatide with sitagliptin or
pioglitazone, all in combination with metformin monotherapy. This combination
is not recommended in current guidance unless a sulphonylurea is
contraindicated or not tolerated, or there is a significant risk of hypoglycaemia
(NICE clinical guideline 87). In addition, DURATION-2 did not include any
European centres. The Committee therefore had reservations about how well
the trial populations reflected current UK clinical practice. The Committee
considered that the nature of the evidence (including the wide mix of
background treatments in some trials) does not allow inferences to be drawn
on a specific place for weekly prolonged-release exenatide in the treatment
pathway as dual- and triple-therapy agents. It concluded that the DURATION
trials were sufficiently relevant to the decision problem to allow use of the data
in evaluating clinical effectiveness, but that caution should be used when
generalising data where the trials differed from normal UK clinical practice.
4.6
The Committee considered the evidence comparing weekly prolonged-release
exenatide with exenatide twice daily (DURATION-1 and DURATION-5). It
considered weekly prolonged-release exenatide to be more effective in
lowering HbA1c than exenatide twice daily and to have similar efficacy in
inducing weight loss and improving quality of life. The Committee concluded
that weekly prolonged-release exenatide is more clinically effective in reducing
HbA1c than the twice-daily preparation and that this appeared consistent across
differing background treatments.
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4.7
The Committee considered the evidence comparing weekly prolonged-release
exenatide with sitagliptin and pioglitazone (DURATION-2). The Committee
concluded that the trial demonstrated that, in combination with metformin,
weekly prolonged-release exenatide was more clinically effective than both
sitagliptin and pioglitazone for the outcomes of HbA1c reduction and weight
loss.
4.8
The Committee considered the evidence comparing weekly prolonged-release
exenatide with insulin (DURATION-3). The Committee noted the absence of
any clinical data comparing weekly prolonged-release exenatide with human
NPH insulin, which is the recommended insulin in NICE clinical guideline 87,
and that 70% of patients in the DURATION-3 study were taking metformin
monotherapy as background treatment (see section 3.3). The Committee
considered weekly prolonged-release exenatide to have greater efficacy than
insulin glargine for reducing HbA1c. The Committee also noted that treatment
with weekly prolonged-release exenatide resulted in weight loss and treatment
with insulin glargine produced weight gain. The Committee concluded that
weekly prolonged-release exenatide is more clinically effective than insulin
glargine in reducing HbA1c, although there is uncertainty about how this can be
applied to UK clinical practice because of the small number of patients in
DURATION-3 trial (30%) who were on standard dual therapy
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The Committee considered evidence from the randomised controlled trial of
weekly prolonged-release exenatide with liraglutide 1.8 mg (DURATION-6) and
the network meta-analysis which compared weekly prolonged-release
exenatide with liraglutide 1.2 mg. The Committee noted that there was
significantly greater HbA1c reduction and weight loss with liraglutide 1.8 mg
than with weekly prolonged-release exenatide. However, the Committee noted
that this dose of liraglutide is not recommended by NICE and accepted the
validity of the network meta-analysis that showed there was no statistically
significant difference between the clinical effects of weekly prolonged-release
exenatide and liraglutide 1.2 mg (the dose that was recommended in NICE
technology appraisal guidance 203). The Committee heard from clinical
specialists that there were no clinically important differences between the
GLP-1 agonists. The Committee therefore concluded that weekly prolongedrelease exenatide and liraglutide 1.2 mg had similar efficacy in the treatment of
type 2 diabetes.
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4.10
The Committee discussed the likely duration of effectiveness of weekly
prolonged-release exenatide. The Committee noted that the clinical trials
provided evidence that the effect of weekly prolonged-release exenatide on
outcomes on reduction in HbA1c and weight loss persisted for up to 3 years but
that no longer-term data are available. Clinical specialists advised that
because GLP-1 agonists initiate a dual physiological response by increasing
insulin secretion and suppressing glucagon secretion, it is difficult to predict the
length of time they will be effective because they could still have an
antihyperglycaemic effect after beta cells have stopped producing insulin. They
further noted that consequently there may be differences in the degree and
duration of effect of weekly prolonged-release exenatide depending on how
long a patient has had type 2 diabetes. The Committee also heard from the
clinical specialists that younger people are increasingly presenting with type 2
diabetes and, although it is not currently known how long weekly prolongedrelease exenatide will be efficacious, glycaemic control could potentially be
maintained for 5 years and possibly up to 15–20 years. If ultimately proven to
have a prolonged therapeutic effect, GLP-1 agonists might even allow some
people who currently need insulin to manage their diabetes without insulin (coadministration with insulin is not presently covered by the UK marketing
authorisations for any of the GLP-1 agonists). The Committee concluded that
there is presently insufficient evidence to determine the duration of the
therapeutic effect of weekly prolonged-release exenatide.
4.11
The Committee discussed the relevance of the surrogate endpoints (notably
HbA1c) used in the clinical trials as predictors of clinical outcomes. The
Committee heard from the clinical specialists that UKPDS data showed that a
1% reduction in HbA1c was associated with a 37% reduction in microvascular
complications and a 16% reduction in myocardial infarction. The Committee
concluded that HbA1c was an appropriate surrogate marker in type 2 diabetes
but noted that there was a need for long-term efficacy and safety data with
weekly prolonged-release exenatide, particularly relating to cardiovascular
outcomes.
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4.12
The Committee discussed the treatment continuation criteria for GLP-1
agonists (NICE clinical guideline 87 and NICE technology appraisal 203),
which specify both a reduction of 1 percentage point HbA1cand weight loss of
at least 3% of initial body weight at 6 months. The Committee noted that the
Association of British Clinical Diabetologists' audit shows that there is a
complex relationship between HbA1c and weight loss and that it is not clear
how much of a fall in HbA1c can be attributed to reduced body weight. The
Committee noted that the evidence for these criteria could be reviewed when
the clinical guideline for type 2 diabetes (NICE clinical guideline 87) is updated.
The Committee therefore concluded that the continuation rules in current NICE
guidance are also appropriate for recommendations on treatment with weekly
prolonged-release exenatide.
4.13
The Committee considered the adverse events associated with weekly
prolonged-release exenatide. The Committee noted that the adverse events
were generally mild to moderate in intensity and that nausea, which was the
most common adverse event, decreased over time. The Committee also noted
that the incidence of hypoglycaemia was low. The Committee concluded that
the adverse-events profile of weekly prolonged-release exenatide was
acceptable.
4.14
The Committee considered the cost effectiveness of weekly prolonged-release
exenatide compared with exenatide twice daily, liraglutide 1.2 mg, pioglitazone,
sitagliptin and insulin glargine in the manufacturer's submission and the
critique and exploratory analyses provided by the ERG. The Committee noted
this model was also used in NICE technology appraisal guidance 203 and was
acceptable, although it noted that these diabetes models are generally rather
outdated because they are based on data that are 20 years old (UKPDS). In
the absence of more recent data, the Committee concluded, with some
reservations, that the CORE model which formed the basis of the
manufacturer's submission was acceptable for assessing the cost
effectiveness of weekly prolonged-release exenatide.
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4.15
The Committee discussed the assumption in the manufacturer's model that
treatment with weekly prolonged-release exenatide will last for 5 years before
a switch to insulin is needed. The Committee noted that there was no clinical
evidence to support this and that the duration was chosen by the manufacturer
for consistency with previous technology appraisals. The Committee
considered the sensitivity analyses on the duration of treatment before patients
switched to insulin. It noted that reducing the treatment duration from 5 years
(in the base case) to 3 years reduced the ICER, and increasing the treatment
duration to 8 years increased the ICER of weekly prolonged-release exenatide
compared with each of the comparators. Based on evidence from the clinical
specialists, the Committee concluded that it is plausible that people may be on
weekly prolonged-release exenatide for 5 years although it still had concerns
over the validity of that assumption, and considered that it could be a
significant underestimate.
4.16
The Committee considered the key drivers of cost effectiveness based on the
manufacturer's deterministic sensitivity analyses. It noted that the effects of
weekly prolonged-release exenatide on HbA1c and weight were key drivers,
and that reducing the efficacy of weekly prolonged-release exenatide to the
lower 95% confidence interval for HbA1c or weight increased the ICERs of
weekly prolonged-release exenatide compared with most comparators. The
Committee was aware that when the lower 95% confidence interval for HbA1c
was used in the sensitivity analysis, the comparison of weekly prolongedrelease exenatide with liraglutide 1.2 mg changed from weekly prolongedrelease exenatide being dominant in the base case to liraglutide dominating in
the sensitivity analysis. The Committee considered this was because of the
similar efficacy of weekly prolonged-release exenatide and liraglutide. The
Committee concluded that the calculated base-case ICERs for weekly
prolonged-release exenatide compared with exenatide twice daily, sitagliptin,
pioglitazone and insulin glargine could be considered robust to sensitivity
analyses, but the ICER compared with liraglutide 1.2 mg was not stable
because the two drugs have similar efficacy and have only modest differences
in cost.
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4.17
The Committee considered the manufacturer's base-case model and noted
that the ICERs for weekly prolonged-release exenatide versus exenatide twice
daily, liraglutide 1.2 mg, pioglitazone, sitagliptin and insulin glargine, plus
additional analyses using costs for human NPH insulin were below £20,000
per QALY gained and that the probabilistic sensitivity analysis also showed
that weekly prolonged-release exenatide had a high probability of cost
effectiveness at £20,000 per QALY gained. The Committee also noted that
these ICERs did not reflect the potential differential cost effectiveness of
weekly prolonged-release exenatide when used at different parts of the
treatment pathway. The Committee therefore considered that the use of weekly
prolonged-release exenatide should be considered separately as part of dual
and triple therapy compared with alternative treatments at these steps in the
pathway in line with the current recommendations for GLP-1 agonists (NICE
clinical guideline 87 and NICE technology appraisal guidance 203), which best
reflect clinical practice in the UK.
4.18
The Committee examined the subgroup analyses according to baseline HbA1c
and baseline body mass index. The Committee noted that weekly prolongedrelease exenatide was cost effective regardless of baseline HbA1c subgroup
but that there seemed to be improved cost effectiveness in the group with
baseline HbA1c of 9% or greater. The Committee heard from clinical specialists
that in clinical practice the glycaemic response to GLP-1 agonists is more
pronounced in people with a higher baseline HbA1c. The Committee noted that
the results according to body mass index were mixed but that the ICER
decreased for all comparisons versus the base case in the subgroup where
body mass index was 35 kg/m2 or greater. The Committee concluded that the
results of the subgroup analysis were consistent with the NICE guidance for
the use of GLP-1 agonists (NICE clinical guideline 87 and NICE technology
appraisal guidance 203) in people with a higher body mass index plus
associated obesity-related problems and people with poorly controlled blood
glucose.
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4.19
The Committee considered a scenario analysis in which the treatment
continuation criteria for GLP-1 agonists were applied (NICE clinical
guideline 87 and NICE technology appraisal guidance 203) instead of the
5-year treatment duration that was applied to all patients in the base case. The
Committee noted that applying the treatment continuation criteria reduced the
ICER of weekly prolonged-release exenatide for all comparisons (sitagliptin,
pioglitazone and insulin glargine). The Committee concluded that the treatment
continuation criteria and definition of metabolic response for GLP-1 agonists
that have been previously applied in NICE guidance would also be relevant to
weekly prolonged-release exenatide.
4.20
The Committee considered the potential use of weekly prolonged-release
exenatide compared with exenatide twice daily and liraglutide as part of triple
therapy in people with a high body mass index (equal to or greater than 35 kg/
m2) who have inadequate glycaemic control (HbA1c equal to or greater than
7.5%) and other obesity-related problems. The Committee considered weekly
prolonged-release exenatide to be more clinically effective than exenatide
twice daily and have similar efficacy to liraglutide 1.2 mg in terms of glycaemic
control. The Committee further noted that weekly prolonged-release exenatide
dominated exenatide twice daily and liraglutide in the base case and continued
to dominate exenatide twice daily in all sensitivity analyses. The Committee
noted that the slightly lower administration costs associated with weekly
prolonged-release exenatide compared with liraglutide were related to the cost
of needles. The Committee concluded that although weekly prolonged-release
exenatide appeared marginally more cost effective than liraglutide 1.2 mg,
weekly prolonged-release exenatide did not offer sufficient evidence of
additional benefits to justify differential recommendation of GLP-1 agonists in
triple therapy. The Committee therefore concluded that weekly prolongedrelease exenatide is a cost-effective alternative to exenatide twice daily and
liraglutide 1.2 mg in triple therapy as currently recommended in NICE
guidance.
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4.21
NICE technology
appraisal guidance
248
The Committee considered the potential use of weekly prolonged-release
exenatide compared with insulin in triple therapy regimens. It noted that GLP-1
agonists (exenatide and liraglutide) are used to delay insulin therapy in
selected patients as recommended in NICE guidance (NICE clinical guideline
87 and NICE technology appraisal guidance 203). The Committee was
satisfied that, despite the use of insulin glargine instead of the less expensive
human NPH insulin in the DURATION-3 trial and the major uncertainty related
to the duration of therapy, weekly prolonged-release exenatide is likely to be as
cost effective as the other GLP-1 agonists compared with starting insulin for
these selected patients. During consultation the Committee received a
comment from a consultee that the recommendation for the use of prolongedrelease exenatide in triple therapy in patients with a body mass index of less
than 35kg/m2 and obesity-related problems; and where therapy with insulin
would have significant occupational implications was too restrictive. The
consultee suggested that prolonged-release exenatide should also be
considered in patients for whom insulin therapy would have a negative impact
on quality of life. The Committee considered that because clinical practice was
broadly in line with NICE clinical guideline 87, there would need to be a good
evidence-based justification for increasing the use of GLP-1 agonists (including
prolonged-release exenatide) in triple therapy beyond that of current NICE
guidance. The Committee concluded that weekly prolonged-release exenatide
should be recommended for use in triple therapy in the same way as the
existing GLP-1 agonists (NICE clinical guideline 87 and NICE technology
appraisal guidance 203).
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4.22
NICE technology
appraisal guidance
248
The Committee considered the potential use of weekly prolonged-release
exenatide as part of dual therapy. It noted that no trial had been carried out by
the manufacturer to compare metformin plus weekly prolonged-release
exenatide with metformin plus sulphonylurea, which is the recommended firstline dual therapy option in NICE clinical guideline 87. The Committee heard
from the clinical specialists that they were concerned about the incidence of
hypoglycaemia associated with sulphonylureas, which they considered to be
underestimated, and that dual therapy alternatives to sulphonylureas would be
welcomed. The Committee discussed a trial of liraglutide that had been
discussed in a previous appraisal, which found no statistically significant
difference between the GLP-1 agonist and a sulphonylurea in reducing HbA1c
when given in combination with metformin (NICE technology appraisal
guidance 203). The Committee concluded that there was no evidence that
weekly prolonged-release exenatide was as effective or more effective than
sulphonylureas, and that weekly prolonged-release exenatide plus metformin
could not be recommended as a substitute for metformin in combination with
sulphonylurea in dual therapy.
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4.23
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248
The Committee discussed the use of weekly prolonged-release exenatide in
people who are unable to take sulphonylureas as a second-line agent in
combination with metformin. The Committee did not consider that metformin in
combination with a GLP-1 agonist was current routine NHS practice and noted
that adding a GLP-1 agonist to metformin in preference to oral alternatives to
sulphonylureas (pioglitazone and DPP-4 inhibitors) had the potential to alter
the established and recommended treatment pathway for managing diabetes,
particularly if sulphonylureas became less commonly prescribed. Therefore,
considerable certainty about the clinical effectiveness, duration of effect and
cost effectiveness would be needed before introducing a new treatment at this
stage in the pathway. The Committee considered that there was high
uncertainty associated with the potential use of weekly prolonged-release
exenatide compared with greater volumes of evidence and clinical experience
for pioglitazone and DPP-4 inhibitors. The Committee further noted that the
DURATION-2 study, which compared weekly prolonged-release exenatide with
pioglitazone and sitagliptin, had a relatively small population with
approximately 165 patients in each treatment arm, and did not have any
European centres. The cost of pioglitazone may also reduce in the near future
because its UK patent protection has recently expired. The Committee also
considered the uncertainty related to the duration of action of this combined
treatment, which could have a major impact on the cost effectiveness. It
concluded that there was at present insufficient evidence to recommend
weekly prolonged-release exenatide in dual therapy for all patients who cannot
tolerate sulphonylureas.
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4.24
NICE technology
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248
The Committee considered the potential place of weekly prolonged-release
exenatide as part of dual therapy compared with liraglutide 1.2 mg in people
who are not able to take either metformin or a sulphonylurea and are also
unable to take pioglitazone or DPP-4 inhibitors (the limited population for
whom liraglutide 1.2 mg is currently recommended as dual therapy). The
Committee considered the similar clinical and cost effectiveness of weekly
prolonged-release exenatide and liraglutide 1.2 mg, and noted that the
alternatives for these patients were limited to monotherapy with an oral
antidiabetic agent or early initiation of insulin therapy. The Committee noted
that any differences in cost effectiveness between GLP-1 agonists were likely
to be too small to justify making differential recommendations for the use of
GLP-1 agonists in dual therapy. The Committee therefore concluded that
weekly prolonged-release exenatide could be an option for dual therapy in
patients who cannot take either metformin or sulphonylureas and are also
unable to take thiazolidinediones and DPP-4 inhibitors. The Committee
considered whether weekly prolonged-release exenatide was innovative and
provided a major change in the management of type 2 diabetes. The
Committee considered the main benefit of weekly prolonged-release exenatide
to be that patients need fewer injections (weekly versus daily), which reduces
the impact of managing type 2 diabetes on the daily lives of patients and
carers. It has been suggested that this benefit may improve adherence
although there is currently no evidence to support this hypothesis. The
Committee concluded that weekly prolonged-release exenatide does not
represent a major change in the management of type 2 diabetes but is a
sustained-release preparation of a currently available treatment.
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4.25
NICE technology
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248
The Committee considered whether NICE's duties under the equalities
legislation required it to alter or to add to its recommendations in any way. The
Committee heard from the patient expert that a particular benefit from this
treatment could be derived for people who need assistance with injections
because of the reduced frequency of injections compared with other therapies.
During consultation the Committee was also made aware that the uptake of
insulin is reportedly low in people of South Asian family origin and there is
evidence that compliance with oral medication is also poor. It was suggested
that weekly prolonged-release exenatide would be a good alternative for these
patients. Poor medical attendance and adherence to treatment was
acknowledged by the clinical specialist, and although the causes were unclear,
it was considered that this might be associated with cultural preference and
concerns about conventional therapy. Nevertheless, the Committee concluded
there was at present no evidence that a weekly injected preparation would
improve treatment adherence or outcomes in any patient group to justify
differential recommendations for weekly prolonged-release exenatide.
Summary of Appraisal Committee's key conclusions
TA248 (STA)
Exenatide prolonged-release suspension for injection in
Section
combination with oral antidiabetic therapy for the treatment of
type 2 diabetes
Key conclusions
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In triple therapy regimens, exenatide prolonged-release suspension for injection (in
combination with metformin and a sulphonylurea, or metformin and a
thiazolidinedione) is recommended as a treatment option for people with type 2
diabetes as described in 'Type 2 diabetes: the management of type 2 diabetes'
(NICE clinical guideline 87). In dual therapy regimens, exenatide prolongedrelease suspension for injection (in combination with metformin or a
sulphonylurea) is recommended as a treatment option for people with type 2
diabetes, as described in 'Liraglutide for the treatment of type 2 diabetes mellitus'
(NICE technology appraisal 203).
1.1, 1.3
4.21,
4.22,
4.25
The Committee considered weekly prolonged-release exenatide to be more
effective than exenatide twice daily and is similar in efficacy to liraglutide 1.2 mg.
The Committee further considered weekly prolonged-release exenatide to be cost
effective compared to exenatide twice daily and liraglutide 1.2 mg and did not see
any reason to depart from the recommendations of current clinical guidance.
Current practice
Clinical need
of patients,
including the
availability of
alternative
treatments
The Committee heard from the clinical specialists that
4.2,
hypoglycaemia associated with sulphonylurea use is considered to 4.23
be underestimated and there is a trend to reduced sulphonylurea
use and to reduced pioglitazone use (because of long-term safety
concerns over bladder cancer).
The patient expert stated that people with type 2 diabetes may be
reluctant to start treatment with insulin or wish to avoid insulin
therapy because of fear of hypoglycaemia and its impact on their
lifestyle.
4.3
The technology
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Proposed
The main benefit of weekly prolonged-release exenatide to
4.25
benefits of the patients is the need for fewer injections (weekly versus daily).
technology
However, the Committee concluded that weekly prolonged-release
exenatide does not represent a major change in the management
How
of type 2 diabetes and no case was made that linked healthinnovative is
related benefits to specific innovative characteristics of weekly
the
technology in prolonged-release exenatide.
its potential to
make a
significant and
substantial
impact on
health-related
benefits?
What is the
position of the
treatment in
the pathway
of care for the
condition?
The Committee concluded that weekly prolonged-release
4.21,
exenatide should be recommended for use in triple and dual
4.22,
therapy in the same way as the existing GLP-1 agonists in NICE
4.25
clinical guideline 87 and NICE technology appraisal guidance 203.
Adverse
effects
The most common adverse drug reactions are mainly
gastrointestinal (nausea, vomiting, diarrhoea and constipation),
injection site reactions, hypoglycaemia (with a sulphonylurea) and
headache. Most adverse reactions are mild to moderate in
intensity. The Committee concluded that the adverse-events
profile of weekly prolonged-release exenatide was acceptable.
2.2,
3.17,
4.13
Evidence for clinical effectiveness
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Availability,
nature and
quality of
evidence
The Committee noted that the evidence in the manufacturer's
submission came from five clinical trials and a network metaanalysis. The randomised controlled trials compared weekly
prolonged-release exenatide with either exenatide 10 micrograms
twice daily, sitagliptin 100 mg, pioglitazone 45 mg, insulin glargine
once daily or liraglutide 1.8 mg. A network meta-analysis was
included to compare the clinical effectiveness of weekly
prolonged-release exenatide with liraglutide 1.2 mg (the dose
recommended in NICE technology appraisal guidance 203). The
Committee noted the significant absence of a trial comparing
weekly prolonged-release exenatide with a sulphonylurea.
Relevance to
general
clinical
practice in the
NHS
The Committee considered the comparators included in the trials
4.4
for dual therapy and triple therapy to be generally appropriate but
noted that insulin glargine was the comparator in the DURATION-3
trial instead of human NPH insulin, which is recommended for
routine use in NICE clinical guideline 87.
The Committee noted that patients in the clinical trials were taking
a mix of different background treatments comprising lifestyle
modification and different drug regimens in three of the trials. It
considered that the nature of the evidence (including the wide mix
of background treatments in some trials) does not allow
conclusions to be drawn on a specific place for weekly prolongedrelease exenatide in the treatment pathway. Although the
Committee had reservations about how well the trial populations
reflected current UK clinical practice, it concluded that they were
sufficiently relevant to the decision problem to allow use of the
data.
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3.1,
3.12,
4.4, 4.5
4.5
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Uncertainties
generated by
the evidence
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248
There was uncertainty about the duration of the therapeutic effect 4.10,
of weekly prolonged-release exenatide because current evidence 4.11
show clinical outcomes persisting for up to 3 years and no longerterm data are available. While HbA1c was considered an
appropriate surrogate marker in type 2 diabetes by the Committee,
it was noted that long-term efficacy and safety data with weekly
prolonged-release exenatide, particularly relating to cardiovascular
outcomes, are needed.
Are there any The UK marketing authorisation for exenatide prolonged-release
clinically
suspension for injection is for the 'treatment of type 2 diabetes
relevant
mellitus in combination with:
subgroups for
metformin
which there is
sulphonylurea
evidence of
differential
thiazolidinedione
effectiveness?
2.1
metformin and sulphonylurea
metformin and thiazolidinedione
in adults who have not achieved adequate glycaemic control on
maximally tolerated doses of these oral therapies'.
Estimate of
the size of the
clinical
effectiveness
including
strength of
supporting
evidence
There was evidence from the DURATION trials that treatment with 4.6,4.7,
weekly prolonged-release exenatide is more clinically effective
4.8, 4.9
than exenatide twice daily in reducing HbA1c (and that this
appeared consistent across differing background treatments) and
has similar efficacy to liraglutide 1.2 mg. The Committee
concluded that, in combination with metformin, weekly prolongedrelease exenatide was more clinically effective than pioglitazone
and sitagliptin. The Committee also concluded that weekly
prolonged-release exenatide is more clinically effective than
insulin glargine although this conclusion is associated with
uncertainty because of the small number of patients in
DURATION-3.
Evidence for cost effectiveness
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Availability
and nature of
evidence
The Committee considered the cost effectiveness of weekly
4.14,
prolonged-release exenatide compared with exenatide twice daily, 4.15
liraglutide 1.2 mg, pioglitazone, sitagliptin and insulin glargine and
the critique and additional analyses provided by the ERG. The
Committee noted that this model was also used in NICE
technology appraisal guidance 203 and was acceptable, although
it noted that these diabetes models are generally rather outdated
because they are based on data that are 20 years old (UKPDS). In
the absence of more recent data, the Committee concluded, with
some reservations, that the CORE model which formed the basis
of the manufacturer's submission was acceptable for assessing
the cost effectiveness of weekly prolonged-release exenatide.
Uncertainties
around and
plausibility of
assumptions
and inputs in
the economic
model
The assumption that in the base case of the manufacturer's model 4.16
that treatment with weekly prolonged-release exenatide will last for
5 years before a switch to insulin glargine is not supported by any
clinical evidence. The assumption was chosen by the
manufacturer for consistency with previous technology appraisals;
changes in duration of effect impacted the ICER.
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Incorporation
of healthrelated
quality-of-life
benefits and
utility values
Have any
potential
significant and
substantial
health-related
benefits been
identified that
were not
included in
the economic
model, and
how have
they been
considered?
NICE technology
appraisal guidance
248
The Committee was aware that the model was also used in NICE
technology appraisal guidance 203 and included utility values for
quality of life and nausea associated with treatment. As a
sensitivity analysis, the model included a disutility value
associated with injection site reactions.
3.20,
4.14
The Committee considered the main benefit of weekly prolonged- 4.24
release exenatide to be that patients need fewer injections (weekly
versus daily), which reduces the impact of managing type 2
diabetes on the daily lives of patients and carers.
Are there
No specific groups were identified in which weekly prolongedspecific
release exenatide was particularly cost effective.
groups of
people for
whom the
technology is
particularly
cost effective?
4.18
What are the The effects of weekly prolonged-release exenatide were driven by
key drivers of changes in HbA1c and weight.
cost
effectiveness?
4.16
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Most likely
costeffectiveness
estimate
(given as an
ICER)
NICE technology
appraisal guidance
248
The Committee noted the ICERs presented in the manufacturer's
submission were not specific to the place of weekly prolongedrelease exenatide in triple and dual therapy regimens. The
Committee did however, consider on the basis of the ICERs
presented in the manufacturer's submission, that weekly
prolonged-release exenatide is likely to be cost effective when
used in the same place in the treatment pathway as twice daily
exenatide and liraglutide 1.2 mg were currently recommended.
4.17
Additional factors taken into account
Patient
access
schemes
(PPRS)
Not applicable to this appraisal.
End-of-life
Not applicable to this appraisal.
considerations
Equalities
considerations
and social
value
judgements
The Committee concluded there was at present no evidence that a 4.25
weekly injected preparation would improve treatment adherence
or outcomes in any patient group to justify differential
recommendations for the use of weekly exenatide.
The restrictions outlined in the recommendations (and also in
NICE clinical guideline 87 and NICE technology appraisal
guidance 203) incorporate appropriate adjustment of BMI by
ethnic group.
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1.1
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5 Implementation
5.1
The Secretary of State and the Welsh Assembly Minister for Health and Social
Services have issued directions to the NHS in England and Wales on
implementing NICE technology appraisal guidance. When a NICE technology
appraisal recommends use of a drug or treatment, or other technology, the
NHS must usually provide funding and resources for it within 3 months of the
guidance being published. If the Department of Health issues a variation to the
3-month funding direction, details will be available on the NICE website. When
there is no NICE technology appraisal guidance on a drug, treatment or other
technology, decisions on funding should be made locally.
5.2
NICE has developed tools to help organisations put this guidance into practice
(listed below).
A costing statement explaining the resource impact of this guidance.
Audit support for monitoring local practice.
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6 Recommendations for further research
6.1
There is currently no available evidence for cardiovascular outcomes with
weekly prolonged-release exenatide. Exenatide Study of Cardiovascular Event
Lowering Trial (EXSCEL) is a trial evaluating cardiovascular outcomes after
treatment with weekly prolonged-release exenatide in patients with type 2
diabetes that is expected to complete in 2017.
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7 Related NICE guidance
Liraglutide for the treatment of type 2 diabetes. NICE technology appraisal guidance 203
(2010).
Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes (partial update of
CG66). NICE clinical guideline 87 (2009).
Type 2 diabetes: the management of type 2 diabetes (partially updated by CG87). NICE
clinical guideline 66 (2008).
Diabetes in pregnancy: management of diabetes and its complications from pre-conception
to the postnatal period. NICE clinical guideline 63 (2008). Continuous subcutaneous insulin
infusion for the treatment of diabetes (review). NICE technology appraisal guidance 151
(2008).
Type 2 diabetes: prevention and management of foot problems. NICE clinical guideline 10
(2004).
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8 Review of guidance
8.1
The guidance on this technology will be considered for review at the same time
as NICE technology appraisal 203 in May 2012.The Guidance Executive will
decide whether the technology should be reviewed based on information
gathered by NICE, and in consultation with consultees and commentators.
Andrew Dillon
Chief Executive
February 2012
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Appendix A: Appraisal Committee members, and NICE
project team
A Appraisal Committee members
The Appraisal Committees are standing advisory committees of NICE. Members are appointed
for a 3-year term. A list of the Committee members who took part in the discussions for this
appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair.
Each Appraisal Committee meets once a month, except in December when there are no
meetings. Each Committee considers its own list of technologies, and ongoing topics are not
moved between Committees.
Committee members are asked to declare any interests in the technology to be appraised. If it is
considered there is a conflict of interest, the member is excluded from participating further in that
appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the members
who attended and their declarations of interests, are posted on the NICE website.
Dr Jane Adam (Chair)
Department of Diagnostic Radiology, St George's Hospital, London
Professor Iain Squire (Vice-Chair)
Consultant Physician, University Hospitals of Leicester
Professor A E Ades
Professor of Public Health Science, Department of Community Based Medicine, University of
Bristol
Dr Jeremy Braybrooke
Consultant Medical Oncologist, University Hospitals Bristol NHS Foundation Trust
Dr Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool
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Professor Jonathan Grigg
Professor of Paediatric Respiratory and Environmental Medicine, Barts and the London School
of Medicine and Dentistry, Queen Mary University London
Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital, Bristol
Dr Sharon Saint Lamont
Head of Quality and Innovation, North East Strategic Health Authority
Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital
Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University
Dr Anne McCune
Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust
Dr Alec Miners
Lecturer in Health Economics, London School of Hygiene and Tropical Medicine
Ms Pamela Rees
Lay member
Dr Ann Richardson
Lay member
Mr Stephen Sharp
Senior Statistician, MRC Epidemiology Unit
Dr Eldon Spackman
Research Fellow, Centre for Health Economics, University of York
Mr Mike Spencer
Assistant Director Patient Experience, Cardiff and Vale University Health Board
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Mr David Thomson
Lay member
Mr William Turner
Consultant Urologist, Addenbrooke's Hospital, Cambridge
Dr Luke Twelves
General Practitioner, Ramsey Health Centre, Cambridgeshire
Dr John Watkins
Clinical Senior Lecturer/Consultant in Public Health Medicine, Cardiff University and National
Public Health Service Wales
Dr Anthony S Wierzbicki
Consultant in Metabolic Medicine/Chemical Pathology, Guy's and St Thomas' Hospitals NHS
Trust
Dr Olivia Wu
Reader in Health Economics, University of Glasgow
B NICE project team
Each technology appraisal is assigned to a team consisting of one or more health technology
analysts (who act as technical leads for the appraisal), a technical adviser and a project
manager.
Linda Landells and Kumar Perampaladas
Technical Leads
Eleanor Donegan
Technical Adviser
Bijal Joshi
Project Manager
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Appendix B: Sources of evidence considered by the
Committee
A The Evidence Review Group (ERG) report for this appraisal was prepared by Warwick
Evidence:
Waugh N, Cummins E, Shyangdan D, et al. Long-acting exenatide in the management of
type 2 diabetes. A single technology appraisal. Warwick Evidence, August 2011
B The following organisations accepted the invitation to participate in this appraisal as consultees
and commentators. They were invited to comment on the draft scope, the ERG report and the
appraisal consultation document (ACD). Organisations listed in I were also invited to make
written submissions. Organisations listed in II and III had the opportunity to give their expert
views. Organisations listed in I, II and III also have the opportunity to appeal against the final
appraisal determination.
I Manufacturer/sponsor:
Eli Lilly and Company
II Professional/specialist and patient/carer groups:
Association of British Clinical Diabetologists
Diabetes UK
National Diabetes Nurse Consultant Group
National Obesity Forum
Royal College of Nursing
Royal College of Pathologists
Royal College of Physicians
South Asian Health Foundation
UK Clinical Pharmacy Association (UKCPA)
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III Other consultees:
Department of Health
Welsh Government
IV Commentator organisations (did not provide written evidence and without the right of appeal):
Bristol Myers Squibb
British National Formulary
Commissioning Support Appraisals Service
Department of Health, Social Services and Public Safety for Northern Ireland
Health Care Improvement Scotland
Medicines and Healthcare products Regulatory Agency (MHRA)
Merck Sharp & Dohme
National Institute for Health Research Health Technology Assessment Programme
Novo Nordisk
Sanofi
Warwick Evidence
C The following individuals were selected from clinical specialist and patient expert nominations
from the non-manufacturer/sponsor consultees and commentators. They gave their expert
personal view on exenatide prolonged-release suspension for injection by attending the initial
Committee discussion and providing written evidence to the Committee. They were also invited
to comment on the ACD.
Professor Jiten Vora, Consultant Endocrinologist, nominated by organisation representing Eli
Lilly and Company – clinical specialist
Dr Peter Davies, Consultant Physician, nominated by organisation representing Association
of British Clinical Diabetologists – clinical specialist
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Mrs Cathy Moulton, Clinical Advisor, nominated by organisation representing Diabetes UK–
patient expert
D Representatives from the following manufacturer/sponsor attended Committee meetings. They
contributed only when asked by the Committee chair to clarify specific issues and comment on
factual accuracy.
Eli Lilly and Company
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NICE technology
appraisal guidance
248
About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and
treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the
guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the
evidence available. Healthcare professionals are expected to take it fully into account when
exercising their clinical judgement. However, the guidance does not override the individual
responsibility of healthcare professionals to make decisions appropriate to the circumstances of
the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers.
Commissioners and providers are reminded that it is their responsibility to implement the
guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have
regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a
way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright
material can be downloaded for private research and study, and may be reproduced for
educational and not-for-profit purposes. No reproduction by or for commercial organisations, or
for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical Excellence
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Copyright © NICE 2012. All rights reserved. Last modified February 2012
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Exenatide prolonged-release suspension for injection in
combination with oral antidiabetic therapy for the treatment of type 2
diabetes
NICE technology
appraisal guidance
248
www.nice.org.uk
nice@nice.org.uk
0845 033 7780
Copyright © NICE 2012. All rights reserved. Last modified February 2012
Page 55 of 55